Metabolic Regulation ofPD-L1 in CD11c+ Cells

CD11c 细胞中 PD-L1 的代谢调节

基本信息

批准号：
10533781
负责人：
HONG DU
金额：
$ 52.06万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-04 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10533781
关键词：
Acid Lipase Amino Acids Antigen Presentation Antigen-Presenting Cells Antigens Binding Blood Bone Marrow CSF1R gene Cell Proliferation Cell Separation Cell physiology Cells Cholesterol Cholesterol Esters Clinical Trials Cross Presentation Cytomegalovirus Cytotoxic T-Lymphocytes Data Dendritic Cells Development Environment Enzymes FRAP1 gene Flow Cytometry Gene Expression Regulation Generations Glucose Glutamine Goals Hematopoietic stem cells ITGAX gene Immune Cell Suppression Immunologic Stimulation Immunosuppression Immunotherapy In Vitro Inflammation Inflammatory Injections Knock-out Ligands Lysosomes Mediating Metabolic Metabolic Pathway Metabolism Molecular Mus Myelogenous Myeloid Cells Neoplasm Metastasis Nonesterified Fatty Acids Nuclear Oncogenic Outcome PD-1 pathway Pathway interactions Peroxisome Proliferator-Activated Receptors Play Proliferating Pyruvate Reactive Oxygen Species Regimen Regulation Role Signal Transduction T-Cell Activation T-Cell Proliferation T-Lymphocyte Testing Triglycerides Tumor Antigens Tumor Immunity Tumor Promotion Up-Regulation Wolman Disease anti-tumor immune response cancer immunotherapy cancer initiation cancer therapy design draining lymph node effector T cell experimental study fatty acid metabolism immune checkpoint improved in vivo mouse model neoplastic cell pre-clinical programmed cell death ligand 1 programmed cell death protein 1 success transcription factor transcriptome sequencing tumor tumor growth tumor microenvironment tumorigenesis

项目摘要

Project Summary/Abstract The long-term goal is to find better intervening approaches to interdict cancer initiation, progression and metastasis. The PD-L1/PD-1 signaling pathway is a critical immune checkpoint mechanism utilized by tumor to escape antitumor immune responses. PD-L1 binds to PD-1 on activated T cells to mediate an inhibitory signal through PD-1-expressing T cells. In comparison, the functional roles of PD-L1 expression in the myeloid compartment are less clear. CD11c+ DCs are well known for their function to capture tumor antigens and cross-present these antigens to T cells in tumor-draining lymph nodes, resulting in the generation of tumor-specific cytotoxic T lymphocytes (CTLs) that contribute to tumor rejection. Interestingly, we have shown that CD11c+ cells isolated from the blood of lysosomal acid lipase (LAL) knockout (lal-/-) mice possess immunosuppression in the absence of antigen presentation, and directly stimulate tumor proliferation in vitro and tumor growth in vivo. Concomitantly, PD-L1 expression was increased in lal-/- CD11c+ cells, which is required for immunosuppression and tumor stimulation. Our observations suggest that the LAL deficiency-induced metabolic switch leads CD11c+ cells to confer tumor stimulation rather than rejection. Based on these observations, this proposal will focus on how PD-L1 expression in lal-/- CD11c+ cells contributes to immune suppression and tumor stimulation during LAL-deficiency. LAL is a key enzyme that hydrolyzes cholesteryl esters and triglycerides in the lysosome of cells to generate free fatty acids (FFAs) and cholesterol. The metabolites of FFAs are ligands for nuclear transcription factor peroxisome proliferator activated receptor  (PPAR), a negative regulator of inflammation. Since LAL is critically involved in fatty acid metabolism, the proposed study will further elucidate the underneath metabolic mechanism by which lal-/- CD11c+ cells influence tumor immunity and stimulation through PD-L1 expression. RNAseq and flow cytometry demonstrated that PD-L1 expression is regulated by glucose/glutamine metabolic processes and mammalian target of rapamycin (mTOR) in lal-/- CD11c+ cells, which is under the control of PPAR. Therefore, the current proposal will test a central hypothesis that LAL/PPAR/mTOR axis-regulated PD-L1 expression plays a key role in lal-/- CD11c+ cells’ immune suppression and tumor stimulation through metabolic reprogramming. To achieve our goals, we will use the unique lal-/- mouse model and the conditional c-fms-rtTA/(TetO)7-CMV-hLAL;lal-/- triple mouse model (c-fms-Tg/KO) in which hLAL is specifically expressed in the myeloid compartment of lal-/- mice. The following specific aims are designed to test the central hypothesis:1) Characterizing the developmental and metabolic regulation of PD-L1 expression in CD11c+ cells; 2) Characterizing PD-L1 expression of CD11c+ cells in regulating T cell proliferation and functions; 3) Characterizing PD-L1 expression of CD11c+ cells in tumor stimulation. The successful outcome will help to design a more efficient regimen to increase the efficacy of PD-L1 cancer immunotherapy by manipulating the metabolic pathway and the immune checkpoint pathway.

项目摘要/摘要长期目标是找到更好的介入癌症倡议，进展和转移。 PD-L1/PD-1信号通路是肿瘤利用的关键免疫切口机制逃避抗肿瘤免疫反应。 PD-L1在活化的T细胞上与PD-1结合以介导抑制信号通过表达PD-1的T细胞。相比之下，PD-L1表达在髓样中的功能作用车厢不太清楚。 CD11C+ DC以捕获肿瘤抗原的功能而闻名跨肿瘤淋巴结中T细胞的交叉抗原，导致产生肿瘤特异性细胞毒性T淋巴细胞（CTL），导致肿瘤排斥。有趣的是，我们已经表明从溶酶体酸脂肪酶（LAL）基因敲除（LAL - / - ）小鼠中分离出的CD11C+细胞在没有抗原表现的情况下免疫抑制，并直接在体外刺激肿瘤增殖体内肿瘤生长。同时，在LAL - / - CD11C+细胞中增加了PD-L1的表达，这是必需的免疫抑制和肿瘤刺激。我们的观察结果表明，LAL缺乏诱导的代谢开关将CD11C+细胞引向会议肿瘤刺激，而不是排斥。基于这些观察，这是建议将重点介绍LAL - / - CD11C+细胞中的PD-L1表达如何有助于免疫抑制和肿瘤在LAL缺乏效率期间的刺激。 LAL是一种将胆固醇酯和甘油三酸酯水解的关键酶细胞的溶酶体产生游离脂肪酸（FFA）和胆固醇。 FFA的代谢物是配体核转录因子过氧化物体增殖物激活受体（PPAR），一个负调节剂炎。由于LAL与脂肪酸代谢非常重要，因此拟议的研究将进一步阐明 LAL - / - CD11C+细胞影响肿瘤免疫力和刺激的代谢机制下通过PD-L1表达。 RNASEQ和流式细胞仪表明，PD-L1表达受到调节 LAL - / - CD11C+细胞中雷霉素（MTOR）的葡萄糖/谷氨酰胺代谢过程和哺乳动物靶在PPAR的控制之下。因此，当前的提案将检验一个中心假设，即 LAL/PPAR/MTOR轴调节的PD-L1表达在LAL - / - CD11C+细胞的免疫抑制中起关键作用和通过代谢重编程刺激肿瘤。为了实现我们的目标，我们将使用独特的LAL - / - 鼠标模型和条件C-FMS-RTTA/（TETO）7-CMV-HLAL; LAL - / - 三重小鼠模型（C-FMS-TG/KO），其中 HLAL在LAL - / - 小鼠的髓样室中特异性表达。设计以下特定目标测试中心假设：1）表征PD-L1表达的发育和代谢调节在CD11C+细胞中； 2）表征CD11C+细胞的PD-L1表达在确定T细胞增殖和功能； 3）表征肿瘤刺激中CD11C+细胞的PD-L1表达。成功的结果将帮助设计一种更有效的方案，以通过操纵来提高PD-L1癌症免疫疗法的效率代谢途径和免疫检查点途径。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

BATF Regulates T Regulatory Cell Functional Specification and Fitness of Triglyceride Metabolism in Restraining Allergic Responses.

DOI：
10.4049/jimmunol.2001184
发表时间：
2021-05-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Xu C;Fu Y;Liu S;Trittipo J;Lu X;Qi R;Du H;Yan C;Zhang C;Wan J;Kaplan MH;Yang K
通讯作者：
Yang K

Endothelial Rab7 GTPase mediates tumor growth and metastasis in lysosomal acid lipase-deficient mice.

内皮 Rab7 GTP 酶介导溶酶体酸性脂肪酶缺陷小鼠的肿瘤生长和转移。